Conventional drug administration methods entail periodic dosing of a therapeutic agent in a formulation that ensures drug activity, stability and bioavailability. These methods include topical administration using salves or ointments for skin applications, parenteral administration by injection, and oral administration by ingestion (e.g. tables, pills, and liquids). These methods reduce drug bioavailability by various factors (particularly the physiological barriers and blood clearance), as drug administration typically leads to a sharp initial increase in drug concentration, followed by a steady decline in concentration as the drug is cleared and/or metabolized. Periodic dosing is required to reach and maintain the drug concentration within the appropriate efficacy range. The consequence of this repeated administration is a drug concentration profile that oscillates over time. Such oscillation and initial burst of drug release are particularly undesirable for drugs that are unstable in the blood stream or gastrointestinal tract, are toxic at high doses or have a narrow therapeutic window.
To resolve these difficulties, efforts have been directed over the last several decades to develop alternative drug carriers for more sustained drug action. Due to the ease of functionalization, low cost and the possibility of mass production, polymers are promising candidates for development of drug delivery systems. In this approach, the drug is dispersed within a polymeric matrix, which is wettable (i.e. capable of imbibing water) and serves to control the rate at which the drug is released. Polymeric delivery vehicles offer several advantages over conventional methods of drug administration, such as localization to the desired target site by implantation, topical application or by ingestion. This increases drug potency and reduces systemic toxicity. Polymeric delivery vehicles also release drugs at a controlled rate, thereby maintaining plasma drug concentration within an appropriate therapeutic window and reducing harmful side effects. Lastly, patient compliance is improved because the discomfort that accompanies periodic dosing is eliminated.
Among different polymers studied for polymeric delivery, chitosan (CS) is one polymer that has received significant interest because of its biocompatibility, biodegradability, non-allergenicity and non-toxicity. Chitosan is created via deacetylation reaction of chitin by treating crustacean animal shells with sodium hydroxide. For medical use, CS can be used to help deliver drugs through the skin.
However, current drug delivery applications of CS are highly limited because CS is insoluble in most solvents. CS is generally soluble in lower pH dilute organic acids, such as acetic acid, formic acid, succinic acid, lactic acid, and malic acid. This makes any CS drug delivery method highly pH-sensitive, and further limits CS application to pH-insensitive drugs. Further, current CS-based drug carriers have limited drug loading capacity and drug release sustainability.
As CS-based drug delivery systems have the benefits of biocompatibility, biodegradability, non-allergenicity and non-toxicity, but are limited by solubility and drug delivery capacities, thus, there exists a need in the art for CS-based drug delivery systems and methods that do not require acidic media for dissolution. There is also a need for CS-based drug delivery systems and methods that can load pH-sensitive drugs with high efficiency, increased drug loading capacity and drug release sustainability.